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Purpose    64 Cu-diacetyl-bis ( N   4 -methylthiosemicarbazone) ( 64 Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with  64 Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during  64 Cu-ATSM IRT.    Methods  Biodistribution was evaluated in HT-29 tumor-bearing mice injected with  64 Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between  64 Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after  64 Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic  64 Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses.    Results  Penicillamine reduced  64 Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after  64 Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic  64 Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine.    Conclusions  We developed a novel strategy to reduce radiation exposure in critical organs during  64 Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other  64 Cu-labeled compounds.

plos one

Controlled Administration of Penicillamine Reduces Radiation Exposure in Critical Organs during 64Cu-ATSM Internal Radiotherapy: A Novel Strategy for Liver Protection